1. Field of the Invention
The present invention relates to a method of purifying dideoxynucleoside and, more particularly, 2',3'dideoxynucleoside-derivatives which have already been authorized or are under assessment as anti-AIDS drugs and anti-virus drugs. 2',3'-Dideoxyinosine (ddI), 2',3'-dideoxycytidine (ddC) and 3'-deoxy-3'-azidothymidine (AZT) have already been authorized as anti-AIDS drugs by the FDA (the Federal Food and Drug Administration).
2. Discussion of the Background
Several methods have been reported for the isolation and purification of 2',3'-dideoxynucleoside derivatives from crude reaction products. One method is purification by recrystallization from an organic solvent (McCarthy et al., J. Am. Chem. Soc., (1966) 88, 1549, Mansuri et al., J. Org. Chem., (1989) 43, 4780 and Robins et al., Tetrahedron Lett., (1984) 25, 367). Another method is purification by silica gel chromatography or by using synthetic adsorption resins (U.S. Pat. No. 3,817,982 and Chu et al., J. Med. Chem., (1990) 33, 1553). When 2',3'-dideoxyadenosine (ddA) is synthesized using adenosine as a starting material, nucleic acid bases such as adenine, which result from the cleavage of the glycoside bond of the starting adenosine, and nucleosides such as adenosine (an unreacted starting material), and deoxyadenosine (nucleic acid derivatives) are produced as by-products. When 2',3'-dideoxyinosine (ddI) is synthesized from inosine as a starting material, nucleic acid bases such as hypoxanthine are produced by the cleavage of the glycoside bond of the starting inosine, and nucleosides such as inosine, which is an unreacted starting material, and deoxyinosine (nucleic acid derivatives) are by-produced. DdA or ddI is isolated and purified from a reaction mixture containing such by-products by any one of several methods which include recrystallization, silica gel chromatography and purification on a resin, these methods being known per se. However, because of the physicochemical similarities between the desired compounds and the by-products, such known separation and isolation methods only produce ddA or ddI as the desired compound in extremely low yields when they are to be obtained in high purity, and when complicated procedures are required. Thus, such methods are not industrially applicable purification methods.
In view of the above, when it is desired to isolate ddA from a mixture of ddA and adenine, adenosine, deoxyadenosine or the like, or when it is desired to isolate ddI from a mixture of ddI and hypoxanthine, inosine, deoxyinosine or the like, by resin purification, a modification which has been attempted is the use of a nonpolar porous resin (for example, "SP-207", manufactured by Mitsubishi Kasei Co.) which is often used for the purification of nucleic acid derivatives. Here an aqueous solution of ddA or ddI (pH 7-10) is contacted with the resin, and ddA or ddI is selectively adsorbed. The adsorbed ddA or ddI is eluted with an alcohol. This technique results in the purification of the ddA or ddI (Japanese Patent Applications Laid-Open Hei 1-98496, Hei 1-175990, Hei 1-165390 and Hei-1-175991). However, the purity and the yield of the desired compounds are not always satisfactory. A need therefore continues to exist for an improved method of purifying ddA or ddI.